Sulfur dioxide (SO2) regulates many physiological processes. Little is known about its roles in neurological disorders. In this study, we investigated the role of endogenous SO2 in the development of febrile seizures (FS) and related brain damages. In the rat model of recurrent FS, we found that endogenous SO2 in the plasma and hippocampus was increased, accompanied by upregulation of aspartate amino-transferase 1 (AAT1) and AAT2, and neuronal apoptosis and mossy fiber sprouting (MFS) in the hippocampus. Preconditioning with low concentration of SO2 (1-10 mu mol/kg) alleviated the neuronal damage, and attenuated neuronal apoptosis and MFS, whereas preconditioning with high concentration of SO2 (100 mu mol/kg) or inhibition of AAT aggravated the neuronal damage, and promoted neuronal apoptosis and MFS in hippocampus of rats with recurrent FS. These data indicate that endogenous SO2 is involved in the development of FS and related brain damage. Preconditioning with low concentration of SO2 may protect neurons from toxicity caused by FS. (C) 2014 Elsevier Ireland Ltd. All rights reserved.